Production of covered tablets

ABSTRACT

The present invention is a process for the production of covered tablets by melt calendering in which the melt containing active ingredient is introduced between two sheets of the covering material into the molding rolls.

The present invention relates to a process for the production of coveredtablets by molding a melt which contains an active ingredient in acalender with counter-rotating molding rolls which have on their surfacedepressions for receiving and molding the tablet composition (meltcalendering).

The production of tablets by calendering a melt containing an activeingredient is disclosed in DE-A 1 766 546 and U.S. Pat. No. 4,880,585.The basis of this process is the embedding of an active ingredient in amelt of a carrier, eg. fatty substances or water-soluble thermoplasticpolymers. The melt is produced by melting the mixture of activeingredient, polymer and, where appropriate, other ancillary substances,for example in an extruder, and molding the melt in a downstream moldingcalender to give tablets, which harden on cooling. The molding calendercomprises a pair of counter-rotating molding rolls which have on theirsurface engravings (depressions) which correspond to the shape of onehalf of the required tablet. The tablet molding takes place in theregion of contact of the two rolls by combination of the tabletcomposition in one depression on one roll with that in the oppositedepression on the other roll.

Most of the tablets on the market are produced as film-coated tablets,ie. a thin layer of water-soluble polymers is applied to the tablets inthe last production step. This film-coating is often indispensable forvarious reasons, because, for example,

a) a taste which is conferred by the active ingredients and/or ancillarysubstances used must be masked until the tablet reaches the stomach,

b) the active ingredient used is unstable to, for example, light,moisture etc.,

c) the tablets require a colored coating for easier identification.

The protective layers (the coating) have to date been applied almostexclusively by spraying on solutions of water-soluble polymers (organicsolvents and/or water) with simultaneous drying. Besides the filmcoating (layer thickness in the micrometer range) which is conventionalnowadays, there is the sugar-coating process in which thick layers,which are sometimes in the millimeter range, of sugar-containingmixtures are applied. These widely used techniques are described invarious textbooks (see H. Sucker, P. Fuchs, P. Speiser: PharmazeutischeTechnologie; 2nd edition, G. Thieme Verlag Stuttgart (1991), pages347-368).

If a coating was required over the tablets produced by melt calenderingit was necessary to apply this coating in a separate step after thetablets had cooled. This took place in a conventional way, for exampleby spraying on in rotating drums, by the dip pipe process or in afluidized bed etc.

The conventional processes for applying coating layers or for sugarcoating all require comparatively very high energy input, because thesolvents used in the spray solutions must be removed again rapidly afterspraying onto the tablets. In addition, a coating process usually takesseveral hours because the spraying rate cannot be set as high as may berequired.

The application of the coating in a separate step thus requiresconsiderable expenditure of time, additional machinery and additionalstaff, which has marked effects on the production costs.

It is an object of the present invention to provide a process for theproduction of covered tablets by melt calendering in which covering ofthe tablets is possible in a simple and cost-saving manner.

We have found that this object is achieved by producing tablets by meltcalendering with the melt containing active ingredient being introducedbetween two sheets of the covering material into the calender moldingrolls.

The present invention therefore relates to a process for the productionof covered tablets by molding a melt containing active ingredient in acalender with two counter-rotating molding rolls which have on theirsurface mutually opposite depressions for receiving and molding thetablet composition, wherein the melt containing active ingredient isintroduced between two sheets of the covering material into the moldingrolls.

The tablets are produced starting from a mixture which contains one ormore pharmaceutical active ingredients and one or more conventionalancillary substances and which becomes a paste or viscous liquid(thermoplastic), and can therefore be extruded, by melting or softeningof at least one component.

The pharmaceutical mixture is then melted in a conventional way,preferably in an extruder, and fed to the molding calender as described,for example, in U.S. Pat. No. 4,880,585.

At the same time as the melt, two sheets which form the coveringmaterial are fed to the molding rolls, which are in contact along asurface line or are located at only a very small distance from oneanother, in such a way that the sheets are each located between moldingroll and melt. Subsequently during the calendering the tabletcomposition is molded to the required tablet shape with, simultaneously,the part forming the covering of the tablets being cut out of the sheetand applied to the tablets. The temperatures prevailing on the moldingrolls, which are generally from 50 to 150° C., result in softening ofthe sheet material and thus covering of the tablets. The sheet materialmelts at the edges of the tablets and thereby envelopes the tabletssingly so that the tablet is completely and uniformly coated with thecovering material.

If necessary, the covered tablets are subsequently subjected to acooling process, for example in an air or cooling bath.

The process according to the invention has the advantage that theindividual processes of granulation, tableting and coating, which takeplace discontinuously in conventional tablet production, are combined ina single process step which, moreover, takes place continuously.Furthermore, the application of the coating requires no additionalenergy input because it takes place at the same time as the tableting(in this case: calendering), which is anyway carried out at elevatedtemperatures.

In a preferred embodiment, sheets suitable for forming a film coating onthe tablets are used so that film-coated tablets are obtained. The layerthickness of the film can be varied over a wide range. This is possiblein the conventional spraying-on only by changing the process times(longer/shorter spraying time). The superiority of the novel process(saving of time) is particularly evident with thicker layers becausethese thick layers can be applied extremely rapidly and very uniformly.In general, sheets with a thickness of about 10 μm to 500 μm are used.It is possible to use sheets which differ in thickness so that there isa different thickness of film coating on the upper and lower halves ofthe tablet, which makes it possible specifically to influence, forexample, the dissolution characteristics of the tablet in thegastrointestinal tract.

The sheet material can be selected from a wide range of materials. Theonly requirement is that the material is pharmaceutically acceptable.The sheet material can be chosen so that the resulting tablet dissolvesin the gastric fluid or the resulting tablet has modified release ofactive ingredient, for example a tablet with enteric coating or a tabletwith a prolonged action, for example a tablet of the sustained releasetype, prolonged release type, repeat release type or delayed releasetype.

Sheet materials which are suitable for producing such film-coatedtablets and which rapidly dissolve in the acidic gastric fluid are, inparticular, gelatin, polyvinyl alcohol, alkylcelluloses such asmethylcelluloses, hydroxyalkylcelluloses such as hydroxyethyl-,hydroxypropyl- or hydroxypropylmethylcelluose, polyvinylpyrrolidone,certain acrylic resins such as copolymers based on dimethylaminoethylmethacrylate and methacrylates (Eudragit E) etc., alone or mixed withone another.

Examples of film formers which can be used according to the inventionfor coatings with modified release of active ingredient arealkylcelluloses such as ethylcellulose, polyvinyl esters such aspolyvinyl acetate, certain acrylic resins such as copolymers based onmethacrylic acid and methacrylate (Eudragit L and S), cellulosephthalates such as cellulose acetate phthalate orhydroxypropylmethylcellulose phthalate etc. The release characteristicscan additionally be influenced by using sheets of different materials,it also being possible to use a plurality of sheets for covering one orboth tablet halves.

When water-soluble sheets are used, thermoplastic polymers such ashydroxyalkylcelluloses, gelatin or acrylic resins have provenparticularly suitable as sheet material. They can be used in a thicknessof about 50 to 150 μm and, in this case, form a thin, very uniformwater-soluble coating on the tablets.

The process according to the invention makes substantially asepticproduction of tablets possible. The melting of the tablet compositionand, if this takes place in an extruder, the intense input of shearenergy into the product kills the microbes in the composition so that itcan be fed as sterile product to the molding rolls. If sterilizedpolymer sheets are then used, and the melt calendering is carried outunder aseptic conditions, for example with sterile air (laminar flow),the tablets are obtained in sterile form. The tablets can then be packedsterile in another process or, which is particularly preferred,blister-packed simultaneously with the molding of the tablets (see thestatements hereinafter). In the latter case, the risk of contaminationof the product with pathogenic microbes is considerably reduced bycomparison with a conventional process with separate packaging.

The sheets can also according to the invention contain another activeingredient. This can be an active ingredient which is not compatiblewith one of the components in the tablet composition. The incompatibleconstituents are kept separate from one another in this way. Theinclusion of an active ingredient in the sheet also makes it possible,however, to release an initial dose owing to the active ingredientcontained in the sheet and then, with the actual tablet, to provideanother single dose or maintenance of the drug concentration.

In another embodiment, the sheets used are those suitable for packagingthe tablets. These are, in particular, water-insoluble thermoformingsheets, the preferred material being polyethylene, polypropylene,polyvinyl chloride, polyethylene terephthalate, polystyrene, aluminum orcoated aluminum. The tablets are in this way immediately sealed in ablister pack. The separate packaging step which is otherwise customaryis thus unnecessary and, moreover, it is possible in this way to packthe tablets aseptically in an extremely simple manner, especially whencare is taken that the outer edges of the tablet strip are sealedairtight.

It has surprisingly emerged that there is not, as expected, vigorousadhesion of the hot tablet composition to the water-insolublethermoforming sheet so that later removal of the tablets from the packwould be impeded or even impossible.

It has proven particularly advantageous for packaging the tablets tocombine a molding roll with the depressions for receiving and moldingthe tablet composition with a smooth roll. This results in "half"tablets which are sealed in a blister pack which has on one sidedepressions for receiving the tablets and is closed on the other sidewith a smooth sheet which can be pulled off. In this case, an aluminumsheet or a sheet of coated aluminum has proven particularly expedientfor closing the pack.

It may also prove to be expedient not to allow the packaged tablets tocool in air, as otherwise usual, but to provide a separate cooling step.Suitable for this purpose is a water bath, stream of cold air etc. Thisprevents the tablets in the pack cooling too slowly, which may lead tosubsequent deformation of the tablets.

It is also possible to use the sheets for the film coating of thetablets and the sheets for the blister-packaging of the tabletssimultaneously. In this case, the melt in the molding rolls is coveredby the sheet for the film coating and simultaneously sealed in thepackaging sheet. This makes it possible to carry out all the basicoperations needed to produce the tablets, namely tableting, coating andpackaging, in a single step which, moreover, takes place in a continuousmanner. This is associated with enormous savings in cost.

In some cases it has proven expedient to coat the molding rolls or thesheets which are used, in particular the outer sides thereof, with amold release agent in order to facilitate detachment of the tablets orthe packaging from the molding rolls. Examples of suitable mold releaseagents are silicone resins, stearic acid, calcium or magnesium stearate,paraffin, cetyl alcohol or lecithins.

It is also possible using the process according to the invention to addfurther additives to the sheets in a simple manner. Examples of suchadditives are colored pigments, it being possible for the upper andlower sides of the tablets or the packaging to differ in color, maskingflavors, plasticizers etc. It is also possible for one or both sheets tobe printed, eg. with numbers, names etc., in order to ensure unambiguousidentification of the tablets by the patients. This has been possible todate only by subsequent printing with ink jet printers.

The shape of the depressions and thus of the tablets can be chosensubstantially as desired. Depressions which are elongate and in theshape of a segment of an ellipsoid, so that oblong tablets andlenticular tablets are obtained, are particularly expedient.

It is also possible, if required, to produce divisible tablets. For thispurpose it is possible to provide a small rib, which is often in themicrometer range, on the bottom of the depressions, which leads toformation of the score in the finished tablets. However, it ispreferable to use at least one molding roll in which the depressions aredivided by at least one bar which extends essentially to the surface ofthe molding roll and forms the score.

The abovementioned mixtures for producing the tablets are, inparticular, mixtures which contain pharmacologically acceptable polymers(with the glass transition temperature of the mixture being below thedecomposition temperature of all the components of the mixture), forexample polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrrolidone(NVP) and vinyl esters, in particular vinyl acetate, copolymers of vinylacetate and crotonic acid, partially hydrolyzed polyvinyl acetate,polyvinyl alcohol, ethylene/vinyl acetate copolymers, poly (hydroxyethylmethacrylate), copolymers of methyl methacrylate and acrylic acid,cellulose esters, cellulose ethers, in particularhydroxypropylcellulose, polyethylene glycol or polyethylene, preferablyNVP copolymers with vinyl acetate, hydroxypropylcellulose andpolyethylene glycols/polyethylene oxides. The K values (H. Fikentscher,Cellulose-Chemie 13 (1932) 58-64 and 71-74) of the polymers are in therange from 10 to 100, preferably 12 to 70, in particular 12 to 35, forPVP preferably 12-35, in particular 12-17.

The polymeric binder must soften or melt in the complete mixture of allthe components in the range from 50 to 180, preferably 60 to 130° C., sothat the composition can be extruded. The glass transition temperatureof the mixture must therefore always be below 180, preferably below 130°C. It is if necessary reduced by conventional pharmacologicallyacceptable plasticizing ancillary substances such as long-chainalcohols, ethylene glycol, propylene glycol, trimethylolpropane,triethylene glycol, butanediols, pentanols, hexanols, polyethyleneglycols, silicones, aromatic carboxylic esters (eg. dialkyl phthalates,trimellitic esters, benzoic esters, terephthalic esters) or aliphaticdicarboxylic esters (eg. dialkyl adipates, sebacic esters, azelaicesters, citric and tartaric esters) or fatty acid esters.

Examples of conventional pharmaceutical ancillary substances, whosetotal amount can be up to 100% by weight based on the polymer, areextenders such as silicates or diatomaceous earth, stearic acid or saltsthereof, eg. the magnesium or calcium salt, methylcellulose, sodiumcarboxymethylcellulose, talc, sucrose, lactose, cereal or corn starch,potato flour, polyvinyl alcohol, also wetting agents, preservatives,disintegrants, absorbents, colorants, flavorings (cf., for example, H.Sucker et al. Pharmazeutische Technologie, Thieme-Verlag, Stuttgart1978). The only condition for suitability thereof is adequate thermalstability.

Pharmaceutical active ingredients mean for the purpose of the inventionall substances with a pharmaceutical effect and minimal side effects aslong as they do not decompose under the processing conditions. Theamount of active ingredient per dose unit and the concentration may varywithin wide limits depending on the activity and rate of release. Theonly condition is that they suffice to achieve the desired effect. Thus,the concentration of active ingredient can be in the range from 0.1 to95, preferably from 20 to 80, in particular 30 to 70, % by weight. It isalso possible to use combinations of active ingredients. Activeingredients for the purpose of the invention are also vitamins andminerals, as well as crop treatment agents and insecticides.

The process according to the invention is suitable, for example, forprocessing the following active ingredients:

acebutolol, acetylcysteine, acetylsalicylic acid, acyclovir, alprazolam,alfacalcidol, allantoin, allopurinol, ambroxol, amikacin, amiloride,aminoacetic acid, amiodarone, amitriptyline, amlodipine, amoxicillin,ampicillin, ascorbic acid, aspartame, astemizole, atenolol,beclomethasone, benserazide, benzalkonium hydroxide, benzocaine, benzoicacid, betamethasone, bezafibrate, biotin, biperiden, bisoprolol,prazosin, bromazepam, bromhexine, bromocriptine, budesonide, bufexamac,buflomedil, buspirone, caffeine, camphor, captopril, carbamazepine,carbidopa, carboplatin, carotenoids such as β-carotene or canthaxanthin,cefachlor, cefalexin, cefatroxil, cefazolin, cefixime, cefotaxime,ceftazidime, ceftriaxone, cefuroxime, celedilin, chloramphenicol,chlorhexidine, chlorpheniramine, chlortalidone, choline, cyclosporin,cilastatin, cimetidine, ciprofloxacin, cisapride, cisplatin,clarithromycin, clavulanic acid, clomipramine, clonazepam, clonidine,clotrimazole, codeine, cholestyramine, cromoglycic acid, cyanocobalamin,cyproterone, desogestrel, dexamethasone, dexpanthenol, dextromethorphan,dextropropoxiphene, diazepam, diclofenac, digoxin, dihydrocodeine,dihydroergotamine, diltiazem, diphenhydramine, dipyridamole, dipyrone,disopyramide, domperidone, dopamine, enalapril, ephedrine, epinephrine,ergocalciferol, ergotamine, erythromycin, estradiol, ethinylestradiol,etoposide, Eucalyptus globulus, famotidine, felodipine, fenofibrate,fenoterol, fentanyl, flavin mononucleotide, fluconazole, flunarizine,fluorouracil, fluoxetine, flurbiprofen, furosemide, gemfibrozil,gentamicin, Ginkgo biloba, glibenclamide, glipizide, clozapine,Glycyrrhiza glabra, guaifenesin, haloperidol, heparin, hyaluronic acid,hydrochlorothiazide, hydrocodone, hydrocortisone, hydromorphone,ipratropium hydroxide, ibuprofen, imipenem, indomethacin, iohexol,iopamidol, isosorbide dinitrate, isosorbide mononitrate, isotretinoin,ketotifen, ketoconazole, ketoprofen, ketorolac, labetalol, lactulose,lecithin, levocarnitine, levodopa, levoglutamide, levonorgestrel,levothyroxine, lidocaine, lipase, lipoic acid, lisinopril, loperamide,lorazepam, lovastatin, medroxyprogesterone, menthol, methotrexate,methyldopa, methylprednisolone, metoclopramide, metoprolol, miconazole,midazolam, minocycline, minoxidil, misoprostol, morphine, multivitaminmixtures or combinations and mineral salts, N-methylephedrine,naftidrofuryl, naproxen, neomycin, nicardipine, nicergoline,nicotinamide, nicotine, nicotinic acid, nifedipine, nimodipine,nitrendipine, nizatidine, norethisterone, norfloxacin, norgestrel,nortriptyline, nystatin, ofloxacin, omeprazole, ondansetron, pancreatin,panthenol, pantothenic acid, paracetamol, penicillin G, penicillin V,phenobarbital, pentoxifylline, phenylephrine, phenylpropanolamine,phenytoin, piroxicam, polymyxin B, povidone-iodine, pravastatin,prednisolone, bromocriptine, propafenone, propranolol, pseudoephedrine,pyridoxine, quinidine, ramipril, ranitidine, reserpine, retinol,riboflavin, rifampicin, rutoside, saccharin, salbutamol, salcatonin,salicylic acid, simvastatin, somatropin, sotalol, spironolactone,sucralfate, sulbactam, sulfamethoxazole, sulpiride, tamoxifen, tegafur,teprenone, terazosin, terbutaline, terfenadine, theophylline, thiamine,ticlopidine, timolol, tranexamic acid, tretinoin, triamcinoloneacetonide, triamterene, trimethoprim, troxerutin, uracil, valproic acid,vancomycin, verapamil, vitamins B₁, B₂, B₄, B₆, B₁₂, D₃, E, K, folinicacid, zidovudine.

In a few cases, solid solutions may form. The term "solid solutions" isfamiliar to the skilled person, for example from the literature cited atthe outset. In solid solutions of pharmaceutically active ingredients inpolymers, the active ingredient is present in a molecular dispersion inthe polymer.

The following examples illustrate the invention without restricting it.

EXAMPLE 1

A mixture of 60.0% by weight of Kollidon VA-64 (BASF)(polyvinylpyrrolidone copolymer with vinyl acetate (60:40)) and 40.0% byweight of lactose monohydrate was extruded in a twin screw extruder(ZSK-40, Werner+Pfleiderer) under the following conditions:

Temperatures:

Shot 1: 80° C.

Shot 2: 100° C.

Shot 3: 130° C.

Shot 4: 130° C.

Dies: 135° C.

Material throughput: 25 kg/h

Screw speed: 160 rpm The melt 5 was introduced together with twopolypropylene sheets 2 about 300 micrometers thick (thermoformingblister sheet) into the molding calender with two molding rolls 1 whichrotate in the direction of the arrows (useful widths of the moldingrolls about 14 cm). The depressions 3 in the molding rolls 1 weredesigned so that oblong tablets (20×8.5 mm) 4 weighing about 1000 mgwere molded from the melt. The material left the calender as strip oftablets packed in PP sheet. The tablets were not sealed singly in thesheet because the molding rolls of the calender were adjusted so thatthey were not in direct contact at any point (spacing about 0.1 mm).After cooling it was easy to remove the PP sheet as a strip about 14 cmwide (7 parallel rows of tablets on the molding roll) from the tablets.In no case was there adhesion of the melt to the PP sheet. It waspossible to seal individual rows of tablets or the tablet strip acrossthe whole width of the molding roll by subsequent welding of the outeredges (exclusion of air).

The calender and molding rolls useful for the present invention can becooled or heated in a manner known per se and the optimum surfacetemperature of the rolls for the relevant processing step can beadjusted in this way.

We claim:
 1. A process for the production of covered tablets byi) mixingone or more pharmaceutically active ingredients and one or moreconventional ancillary substances to give a pharmaceutical mixture, ii)melting the pharmaceutical mixture to give a melted tablet composition,and iii) molding the melted tablet composition in a calender withcounter-rotating molding rolls at least one of which molding rolls hason its surface depressions for receiving and molding the melted tabletcomposition,which process comprises a) introducing the melted tabletcomposition into the calender between two sheets of covering material,which covering material comprises a polymer selected from the groupconsisting of polyvinyl alcohol, alkylcellulose, hydroxy alkylcellulose,cellulose ester, carboxymethylcellulose, cellulose phthalate, polyvinylpyrrolidone, polyvinyl ester, acrylic resins, and mixtures thereof, b)applying the covering material to the melted tablet compositionsimultaneously to the molding of the tablet composition into therequired tablet shape, c) cutting out of the two sheets of coveringmaterial the parts forming the cover of the tablet simultaneously to themolding of the tablet composition into the required tablet shape,wherebythe tablets are enveloped singly by the coating material to give atablet completely and uniformly coated by the covering material.
 2. Theprocess of claim 1, wherein the coating material further comprises anactive ingredient.
 3. The process of claim 1, wherein the coveringmaterial provides an enteric coating or a coating for modified releaseof active ingredient.
 4. The process of claim 1, wherein the moldingrolls of the calender have different depressions.
 5. The process ofclaim 1, wherein the calender has one molding roll with depressions andone smooth molding roll.
 6. The process of claim 1, wherein the calenderhas at least one molding roll having depressions which are divided by atleast one bar which extends essentially to the surface of the moldingroll and forms a score to give divisible tablets.
 7. The process ofclaim 1, wherein the calender has molding rolls which are coated with amold release agent.
 8. The process of claim 1, further comprising thatthe covered tablets are cooled for hardening.
 9. The process of claim 1,wherein the different sheets of covering material differ from oneanother in their material or in their thickness.
 10. The process ofclaim 1, wherein the coating material further comprises colored pigmentsor masking flavors or a release agent.
 11. A process for the productionof covered tablets byi) mixing one or more pharmaceutically activeingredients and one or more conventional ancillary substances to give apharmaceutical mixture, ii) melting the pharmaceutical mixture to give amelted tablet composition, and iii) molding the melted tabletcomposition in a calender with counter-rotating molding rolls at leastone of which molding rolls has on its surface depressions for receivingand molding the melted tablet composition,which process comprises a)introducing the melted tablet composition into the calender between twosheets of covering material, which covering material comprisespolyethylene, polypropylene, polyvinyl chloride, polyethyleneterephthalate, polystyrene, aluminum or coated aluminum, b) applying thecovering material to the melted tablet composition simultaneously to themolding of the tablet composition into the required tablet shape,wherebythe tablets are enveloped singly by the coating material to give tabletssealed in a blister pack.
 12. The process of claim 11, wherein thedifferent sheets of covering material differ from one another in theirmaterial or in their thickness.
 13. The process of claim 11, wherein thecoating material further comprises colored pigments or masking flavorsor a release agent.
 14. The process of claim 11, wherein the moldingrolls of the calender have different depressions.
 15. The process ofclaim 11, wherein the calender has one molding roll with depressions andone smooth molding roll.
 16. The process of claim 11, wherein thecalender has molding rolls which are coated with a mold release agent.17. A process for the production of covered tablets byi) mixing one ormore pharmaceutically active ingredients and one or more conventionalancillary substances to give a pharmaceutical mixture, ii) melting thepharmaceutical mixture to give a melted tablet composition, and iii)molding the melted tablet composition in a calender withcounter-rotating molding rolls at least one of which molding rolls hason its surface depressions for receiving and molding the melted tabletcomposition,which process comprises a) introducing the melted tabletcomposition into the calender between two sets of two sheets of coveringmaterial,the inner set of sheets directly facing the melted tabletcomposition consisting of a covering material which comprises a polymerselected from the group consisting of polyvinyl alcohol, alkylcellulose,hydroxy alkylcellulose, cellulose ester, carboxymethylcellulose,cellulose phthalate, polyvinyl pyrrolidone, polyvinyl ester, acrylicresins, and mixtures thereof, and the outer set of sheets consisting ofa covering material which comprises polyethylene, polypropylene,polyvinyl chloride, polyethylene terephthalate, polystyrene, aluminum orcoated aluminum, b) applying the covering material of the inner set ofsheets and the outer set of sheets to the melted tablet compositionsimultaneously to the molding of the tablet composition into therequired tablet shape, c) cutting out of the two inner sheets ofcovering material the parts forming the cover of the tabletsimultaneously to the molding of the tablet composition into therequired tablet shape, whereby the tablets are enveloped singly by thecoating material to give a tablet completely and uniformly coated by thecovering material of the inner set of sheets, and d) applying thecovering material of the outer set of sheets to the coated melted tabletcomposition simultaneously to the molding of the tablet composition intothe required tablet shape, whereby the tablets are enveloped singly bythe coating material of the outer set of sheets to give tablets sealedin a blister pack.
 18. The process of claim 17, wherein the differentsheets of covering material differ from one another in their material orin their thickness.
 19. The process of claim 17, wherein the moldingrolls of the calender have different depressions.
 20. The process ofclaim 17, wherein the calender has one molding roll with depressions andone smooth molding roll.